Beneficial effects of ACE-inhibition with zofenopril on plaque formation and low-density lipoprotein oxidation in watanabe heritable hyperlipidemic rabbits

详细信息    查看全文

• 作者：Napoli ; Claudio ; Cicala ; Carla ; D'Armiento ; Francesco P. ; Roviezzo ; Fiorentina ; Somma ; Pasquale ; et. al.
• 关键词：Zofenopril ; WHHL rabbit ; LDL oxidation ; Platelet ; Antioxidants ; Atherogenesis
• 刊名：General Pharmacology
• 出版年：1999
• 出版时间：December, 1999
• 年：1999
• 卷：33
• 期：6
• 页码：467-477
• 全文大小：659 K

文摘

The effects of angiotensin-converting enzyme (ACE)-inhibition with zofenopril on the development of atherosclerosis and low-density lipoprotein (LDL) oxidation were determined in Watanabe Heritable Hyperlipidemic (WHHL) rabbits. Rabbits received either placebo (n = 6) or 0.5 mg/kg/day of zofenopril (n = 6). After 6 weeks of treatment, the computer-assisted analysis revealed that zofenopril reduced the aortic and common carotid corrected cumulative lesion area by 34 % and 39 % , respectively (p < 0.05 vs placebo-treated group). The intimal/medial ratio of the largest fatty streaks was 0.426 ± 0.158 in the zofenopril-treated group and 0.875 ± 0.238 in the placebo-treated group (p < 0.05). Furthermore, we found in the zofenopril-treated group smaller lesions with an intimal/medial ratio of zofenopril also reduced plasmatic LDL oxidation, as shown by significant reduction of malondialdehyde content (p < 0.01) and relative agarose gel mobility (p < 0.05), as well as by the prolongation of the lag-time (p < 0.05). Compared to zofenopril-treated rabbits, arterial sections of the placebo-group had significant increase in the intimal presence of macrophages-derived foam cells (p < 0.05), ox-LDL (p < 0.01), and native LDL (p < 0.01) detected by immunocytochemistry with RAM-11, MDA2 and NP1533975 monoclonal antibodies, respectively. To investigate the amount of platelet accumulation in the atherosclerotic plaque we also measured platelet-associated radioactivity. Autologous platelets were labeled with ¹¹¹Indium-oxine and injected intravenously. After 2 hours, WHHL were sacrificed and arterial sections were counted for platelet-associated radioactivity. In the placebo-treated group, platelet radioactivity was 0.52 ± 0.12 equivalent of radioactivity per mg of tissue in the common carotid and 0.25 ± 0.18 in the abdominal aorta; in contrast, rabbits treated by zofenopril had 0.20 ± 0.12 in the common carotid and 0.06 ± 0.01 in the abdominal aorta. These data indicate that ACE-inhibition with zofenopril has antiatherosclerotic and antioxidant effects in WHHL-rabbits. Our results also shows that these effects could be linked to a reduced wall-associated platelet deposition at the site of atherosclerotic lesions.